Substituted thiocyano pyrroles,fungicidal preparations containing these compounds as active ingredients and methods of using the same

ABSTRACT

SUBSTITUTED DITHIOCYANOPYRROLES HAVE BEEN FOUND TO BE USEFUL AS ANTIFUNGAL AGENTS FOR COMBATING PLANT HARMFUL FUNGI.

United States Patent ()1 ice 3,663,701 Patented May 16, 1972 US. ,Cl. 424-274 3 Claims ABSTRACT OF THE DISCLOSURE Substituted dithiocyanopyrroles have been found to be useful as antifungal agents for combatting plant harmful fungi.

This application is a division of my copending application Ser. No. 602,598, filed Dec. 19, 1966, and now abandoned.

The present invention relates to a compound with the following formula or a salt of same, in which R is a hydrogen atom, a straight, a branched or a cyclic hydrocarbon chain, possibly with an amino group or a halogen group, an ester group or a hydroxy alkyl,

R and R both are a thiocyano group, or one is, and the other is a hydrogen atom or an acyl group,

R and R are chosen among hydroxy alkyl groups, hydrogen atoms or alkyl groups.

Compounds or mixtures of compounds under the above-mentioned formula have proved to be very efficient for use against formation of fungi or scabs on trees and plants. Positive effects have also been established when dressing seeds, the compounds or mixtures of the compounds then having considerable advantages compared with mercury. The reason for this is that the compounds are less toxic.

Very good results were obtained with N-phenyl ot,ot'- dithiocyanopyrrole and with its corresponding N-parachlorophenyl homologue. These compounds, and in particular the N-p-chloro-phenyl derivative are active against Venturz'a inaequalz's, Fusarium culmorum and also against Podosphaera leucotricha (apple powdery mildew).

Also for pharmaceuticals, compounds or mixtures of compounds falling under the above-mentioned formula have proved to be useful as fungicides and antiseptics, in that the growth of skin fungi is prevented, and bacteria are killed. When using it as a pharmaceutical, it is extremely appropriate to utilize a liquid plastic dressing as a carrier for the compound or mixture of compounds used. An example of an appropriate plastic dressing is polybutoxy ethyl methacrylate. When a compound or a mixture of compounds is used, the actual compound or the compounds comprised in the mixture can be used, or salts of the compound or compounds can be used. The salts can consist of hydrochloride, sulphate, acetate etc.

Depending upon the circumstances under which they are to be used, the compounds or salts can be mixed with a appropriate carrier, which can be either solid, semisolid or liquid. The carrier itself can, of course, consist of a number of different components.

When producing substituted thiocyano pyrrole, one or two thiocyano groups are added to a substituted or an unsubstituted pyrrole ring, of which the substituents then are not thiocyano groups, by allowing free thiocyanogen to react with the pyrrole ring. The free thiocyanogen can be obtained as a reaction between an alkali metal thiocyanate, or an ammonium thiocyanate and an appropriate oxidizer, such as halogen, a monochlorocarbamide, or a dichlorocarbamide. Also electrolytic oxidation can be used. A further alternative for forming free thiocyanogen is to decompose a cyanate of a heavy metal, such as copper. At such a decomposition it is appropriate to have a catalyst, such as aluminium trichloride or aluminium tricyanate. The formation of the free cyanogen can appropriately take place in a solvent, which can be formic acid, acetic acid, methyl acetate, chloroform, carbon tetrachloride, methanol or hydrochloric acid.

The thiocyano groups can also be added to the pyrrole ring through Sandmeyers method, or by treating a pyrrole derivative with a halogen thiocyanogen.

In the following, 16 different examples of methods of producing substituted thiocyano pyrroles according to the present invention will be given.

Example 1.N-methyl-a,a'-dithiocyanopyrrole Three hundred grams of potassium thiocyanate and 500 ml. of methanol were placed in a flask fitted with a mechanical stirrer and a thermometer, then chilled in a Dry Ice-acetone bath to about 65 C. The mixture was stirred and kept below 55 C., while a chilled bromine solution, containing 74.5 ml. of bromine in 200 ml. of methanol, was added from a dropping funnel. A solution of 48.6 g. of redistilled N-methylpyrrole (B.P. 114ll7 C.) in 200 ml. of methanol, also chilled to 65 C., was added as rapidly as possible to the above solution. After stirring for about 40 min. after all N- rnethylpyrrole solution was added, the temperature of the reaction mixture was about -40 C. The mixture was poured into 1000 ml. of water and agitated for about 0.5 hours. The precipitate of N-methyl-a,a'-dithiocyanopyrrole was collected on a Biichner funnel, washed with water, dried and recrystallized from alcohol to yield 91 g., M.P. 118-120 C. By evaporation of the mother liquid an additional crude product was obtained which weighed 18 grams.

C- H N S S-calculated, 32.8%; Found, 32.2%.

Example 2.u,a'-Dithiocyanopyrrole The procedure according to the present example corresponds to the procedure of Example 1 with the exception of that the following chemicals Were used: 150 g. of potassium thiocyanate dissolved in 200 ml. of methanol, 34 m1. of bromine dissolved in 50 ml. of methanol, 24.8 g. of pyrrole dissolved in ml. of methanol.

The reaction mixture was poured onto 200 g. of crushed ice and the u,u'-dithiocyanopyrrole was collected on a Biichner funnel, washed with water, dried and recrystallized from water. Melting point l14-1l6 C.

C H N S S--calculated, 35.4%; found, 35.2%.

Example 3.N butyl-a,a'-dithiocyanopyrrole The procedure as in Example 1 with the exception of that the following chemicals were used: 25 g. of potassium thiocyanate dissolved in 100 ml. of methanol, 6.5 ml. of bromine dissolved in 50 ml. of methanol and 6.1 g. of N-butylpyrrole B.P. at 15 mm. Hg 62-70 C. dis solved in 50 ml. of methanol.

The reaction mixture was poured onto 200 g. of crushed ice, and the N-butyl-a,a'-dithiocyanopyrrole was extracted with two portions of chloroform, each of 50 ml. The solution was dried, filtered and evaporated under reduced pressure. The residue was a thick oil which after standing in a refrigerator for some time solidified. The substance had a M.P. of 24-28 C.

C H N S Scalculated, 27.9%; found, 25.4%.

Example 4.N- fl-hydroxyethyl a,u'-dithiocyanopyrrole The procedure as in Example 1 with the exception of that the following chemicals were used: 25 g. of potassium thiocyanate dissolved in 100 ml. of methanol, 6.5 g. of bromine dissolved in 50 ml. of methanol and 5.5 g. of N-(fl-hydroxyethyl)-pyrrole B.P. at 3 mm. Hg 66-76 C. dissolved in 50 ml. of methanol.

The reaction mixture was worked up as in Example 2. The N-(fl-hydroxyethyl)-a,u'-dithiocyanopyrrole was recrystallized in alcohol. Melting point 78-80 C.

C H N OS Scalculated, 28.5%; found, 28.3%.

Example 5.--N-cyclohexyl-a,a-dithiocyanopyrrole The procedure as in Example 1 with the exception of that the following chemicals were used: 25 g. of potassium thiocyanate dissolved in 100 ml. of methanol, 6.3 ml. of bromine dissolved in 50 ml. of methanol, 7.1 g. of N-cyclo-hexylpyrrole, B.P. at 3 mm. Hg 68-74 C. dissolved in 50 ml. of methanol.

The reaction mixture was Worked up as in Example 3. The residue was crystallized in alcohol, and had a M.P. 66-68 C.

C H N S Scalculated, 24.3%; found, 23.5%.

Example 6.N-benzyl-a,a-dithiocyanopyrrole The procedure as in Example 1 with the exception of that the following chemicals were used: 18 g. of potassium thiocyanate dissolved in 50 ml. of methanol, 5.9 g. of bromine dissolved in 50 ml. of methanol and 5.7 g. of N-benzylpyrrole, B.P. at mm. Hg 123l30 C. dissolved in 50 ml. of methanol.

The reaction mixture was worked up as in Example 2. The product was recrystallized in benzene-ligroin. M.P. 9396 C.

C H N S Scalculated, 22.6%; found, 22.8%.

Example 7.N-phenyl-a,u'-dithiocyanopyrrole The procedure as in Example 1 with the exception of that the following chemicals were used: 25.2 g. of potas sium thiocyanate dissolved in 50 ml. of methanol, 6.2 ml. of bromine dissolved in 50 ml. of methanol and 7.2 g. of N-phenylpyrrole, B.P. at 15 mm. Hg 1l0115 C. and M.P. 60-61 C., dissolved in 50 ml. of methanol.

The reaction mixture was worked up as in Example 2. The product was recrystallized in benzene-ligroin. M.P. l62-164 C.

C H N S Scalculated, 24.9% found, 24.7%.

Example 8.a-Thiocyano-uU-acetylpyrrole The procedure as in Example 1 with the exception of that the following chemicals were used: 24 g. of potassium thiocyanate dissolved in 50 ml. of methanol, 5.8 ml. of bromine dissolved in 50 ml. of methanol and 8.5 g. of methyl-a-pyrrylketone, M.P. 92-93 C. dissolved in 50 ml. of methanol.

The reaction mixture was worked up as in Example 2. The product was recrystallized in benzene-ligroin, M.P. 110-138 C. The sulphur content agrees with the calculated. The possibility of an isomeric mixture seems to be probable. After repeated recrystallizing, however, the M.P. was raised to 142-143 C.

C H N OS: Scalculated, 19.3%; found, 19.2%.

Example 9.N-methyl-a-thiocyanopyrrole 75 g. of potassium thiocyanate and 150 ml. of methanol were placed in a flask fitted with a mechanical stirrer and a thermometer, then chilled in a Dry Ice-acetone bath to about C. The mixture was stirred and kept below -55 C. while a chilled bromine solution, containing 16.5 ml. of bromine in 50 ml. of methanol was added from a dropping funnel. The stirring was continued for a further 10 min. after all bromine solution was added. This reaction mixture was then added to a solution of 24.3 g. of N-methylpyrrole (B.P. 114-117 in 200 ml. of methanol also chilled to C. After stirring for about 50 min. the temperature of the reaction mixture was about '30 C. and then poured into 200 ml. of a saturated salt solution. After extracting the solution with two 50-ml. portions of chloroform, the latter was dried, filtered and distilled. The boiling point of the solution was 108-110" C. at 13 mm. Hg.

C H N S: Scalculated, 23.2%; found, 23.2%.

Example 10.2,5-dimethyl-3,4-dithiocyanopyrrole The procedure as in Example 1 with the exception of that the following chemicals were used: 60 g. of potassium thiocyanate dissolved in ml. of methanol, 13.8 ml. of bromine dissolved in 50 ml. of methanol and 14.1 g. of 2,5-dimethylpyrrole, B.P. 129-131 C. dissolved in 40 ml. of methanol.

The reaction mixture was Worked up as in Example 2. The product was recrystallized from ether-ligroin and then from benzene-ligroin, M.P. l34-l36 C.

C H N S -Calculated: S, 30.6%; found: S, 30.2%.

Example ll.-N-ethyl-2,5-dimethyl- 3 ,4-dithiocyanopyrrole The procedure as in Example 1 with the exception of that the following chemicals were used: 20 g. of potassium thiocyanate dissolved in 25 ml. of methanol, 8.1 ml. of bromine dissolved in 25 ml. of methanol and 7.0 g. of N-ethyl-2,5-dimethylpyrrole, B.P. at 10 mm. Hg 61 C. dissolved in 25 ml. of methanol.

The reaction mixture was worked up as in Example 2. The product was recrystallized in benzene, M.P. 132- 133 C.

C H N S Calculated: S, 27.0%; found: S, 27.1%.

Example l2.N-propyl-2,S-dimethyl-3,4-dithiocyanopyrrole The procedure as in Example 1 with the exception of that the following chemicals were used: 20 g. of potassium thiocyanate dissolved in 25 ml. of methanol, 8.1 ml. of bromine dissolved in 25 ml. of methanol and 7.0 g. of N-propyl-Z,S-dimethylpyrrole, B.P. at 15 mm. Hg 78-83 C. dissolved in 25 ml. methanol.

The reaction mixture was worked up as in Example 2. The product was recrystallized in benzene-ligroin, M.P. 5558 C.

C H N S .Calculated: S, 25.5%; found: S, 24.9%.

Example 13.N-butyl-2,5-dimethyl-3,4-dithiocyanopyrrole The procedure as in Example 1 with the exception of that the following chemicals were used: 20 g. of potassium thiocyanate dissolved in 25 ml. of methanol, 8.1 ml. of bromine dissolved in 25 ml. of methanol and 7.5 g. of N-butyl-Z,S-dimethylpyrrole, B.P. at 13 mm. Hg 83-85 C. dissolved in 50 ml. of methanol.

The reaction mixture was worked up as in Example 3. The residue was recrystallized in benzene-ligroin M.P. 82-83 C.

C H N S Calculated: S, 24.2%; found S, 23.8%.

Example l4.-N-(;8-hydroxyethyl)2,5-dimcthyl-3,4- dithiocyanopyrrole The procedure as in Example 1 with the exception of that the following chemicals were used: 20 g. of potassium thiocyanate dissolved in 25 ml. of methanol, 8.1 ml. of bromine dissolved in 25 ml. methanol. 7.0 g. N-(B- hydroxyethyl)-2,5-dimethylpyrrole, B.P. at 7 mm. Hg. 112-113 C. dissolved in 50 ml. of methanol.

The reaction mixture was worked up as in Example 2. The product was crystallized in benzene, M.P. 153- 156 C.

C H N OS -Calculated: S, 25.3%; found: S, 24.8%.

Example 15.N-carbmethoxymethyl-2,5- dimethyl-3,4-dithiocyanopyrrole The procedure as in Example 1 with the exception of that the following chemicals were used: 25 g. of potassium thiocyanate dissolved in 100 ml. of methanol, 6.2 ml. of bromine dissolved in 50 ml. of methanol and 8.3 g. N-Carbmethoxy-2,5-dimethylpyrrole, HP. at 12 mm. Hg 126 C., M.P. 4246 C. dissolved in 50 ml. of methanol.

The reaction mixture was worked up as in Example 2. The product was recrystallized in benzene-ligroin, M.P. 131-135 C.

C H N O S .Calculated: S, 22.2%; found, S, 22.3%.

Example 16.-N-(B-aminoethyl)-2,5-dimethyl-3,4- dithiocyanopyrrole The procedure as in Example 1 with the exception of that the following chemicals were used: 20 g. potassium thiocyanate dissolved in 25 ml. of methanol, 8.1 ml. of bromine dissolved in 25 m1. of methanol and 7.0 g. of N-(fl-aminoethyl)-2,5-dimethylpyrrole, B.P. at 10 mm. Hg 106 C. dissolved in 50 ml. of methanol.

The reaction mixture was worked up as in Example 2. The product was recrystallized in alcohol.

C H N S .Calculated: S, 30.8%; found: S, 30.1%.

Example 17.N-p-chlorophenyl-a,oU-dithiocyanopyrrole The procedure as in Example 1 with the following exceptions: Chemicals: 8.5 g. of potassium thiocyanate in 50 ml. of methanol, 2.7 ml. of bromine in 25 ml. of methanol and 3 g. of N-p-chlorophenylpyrrole in 75 ml. of methanol.

Reaction temperature: 25 to -30 C.

The reaction mixture was worked up as in Example 2. The product was recrystallized from alcohol. Melting point 133-135 C.

C H ClN S :Scalculated, 21.8%; found, 21.3%.

Example 18 In the present example the substances according to Examples 1, 2, 3, 5, 6 and 7 were tested. Each substance as ground very carefully during minutes. To the ground substance 3 mg. of a surfactant and 10 ml. of water were added. A few drops of a suspension of the substances were brought on two glass slideszA few drops of spores of Fusarium culmorum (cultured on agar) or Venturia inaequalis (collected from infected apple leaves) were mixed with the substances.

These mixtures were incubated during 48 hours. The negative logarithms of the concentration which gave complete inhibition of germination are summarized in the following table:

Vent. inueq.

N-benzyl-a,a'-dithiocyanopyrrole N-phe11yl-a,a-dithi0cyanopyrro1e N-p'chlorophenyl-a,a-dithiocyano pyrrole Example 19 Suspensions (prepared as described in Example 18) of substances were sprayed on the lower sides of three tomato leaves (cultivar Bonny Best), placed into water (50 ml. bottles). Three bottles were used for each concentration. After drying, the lower sides of the leaves were 6 infected by spraying them with a suspension of zoospores (100,000 ml.) of Phytophthora infesrans, obtained from sporangia cultured on potato tubers.

The bottles containing the leaves were placed in climate rooms, where during 24 hours the temperature was 15 C., the rel. humidity 95%, the room dark, and where during 2 x 24 hours the temperature was 18 C., re]. humidity 85% and the room continuous fluorescent lit by 3000- 6000 lux. The results were assessed by estimation of the beginning of growth of dark mycelium on the leaves. In the following table the results are expressed in percent of the infection on control leaves, non-treated with a chemical.

E Concentration at- Substance ample 10' 10- 10'- N-methyl-a,a'-dithiocyanopyrrole 1 0 30 70 N-cyelohexyl-a,a'-dithioeyanopyrrole.. 5 4 17 51 N-phenyl-a,a'-dithiocyanopyrrole 7 19 27 51 N-benzy1-a,a-dithiocyanopyrrole 6 12 18 76 N-p-ehlorophenyl-a,a-dithiocyanopyrrole 17 15 29 100 Example 20 pressed in percent of the growth of cycelium on shoots infected in the same way but not treated with a chemical.

Ex- Preven- Concentration atamtive or Substance ple Gurative 10- 10' 10* a,a-dithiocyanopyrrole 2 P 8 0 2 P 1 19 2 C 10 53 N -methy1-a,a -dithiocyan0- pyrrole 1 P 0 0 1 O 27 59 N-cyclohexyl-cz,a-dithioeyan0 pyrrole P 0 0 N-pheny1-a,a'-d cyanopyrrole 7 P 1 16 N-benzyl-a,a'-dithiocyanopyrrole 6 P 4 6 Captan P 0 0 P 0 29 Example 21 The leaves of about 10 cm. high young celery plants (cultivar Balder) were sprayed with appropriately diluted suspensions of the substances. Each concentration was applied on 6 plants. After treatment the plants were infected by spraying with a suspension of spores (150,000/ml.) of Septoria apii collected from infected leaves. The plants were incubated during 14 days in a climate room (18 C.; 16 hours light, 8 hours dark; high humidity).

The results are obtained by estimating the spots per leaf and expressing their number in percent of that observed on non-treated but equally infected control leaves.

Example 22 10 g. of N-methyl-a,a'-dithiocyanopyrrole together with 10 g. of talcum were ground in a glass mill. 20 mg. of this preparation were mixed with 5 g. of beet seed naturally infected with Thoma betae. The seeds were sown in sterilized soil, which was kept at 10 C. during 12 days in an ice box and then 12 days in a Wisconsin tank in the green house (soil temp. 10 C.). Two experiments showed 7 8 that apparently 97% and 100% respectively of the seed- The results of the test are put together in the following lings were protected against Thoma betae. table. M4

Test organisms m M. E. Cami. As; our. coli 1 alb. niger a,a-dithioeyanopyrrole 2 40 8 8 4O N-butyl-a,a-dithiocyanopyrrole 3 40 40 8 40 N-benzyl-a,a-dithioeyanopyrrole. 6 40 40 4 8 N-phenyl-a,a'-dithioeyanopyrrole. 7 8 40 a-thioeyano-d-aeetyl pyrrole 8 100 100 40 40 N-methyl-ot,d-dithioeyanopyrrole 1 40 8 8 40 1 Test solution 4.

1 Test solution 6.

Example 23 In the above table the mark indicates that the 20 highest concentration has not caused any inhibition in- 10 g. of a,ot-dithiocyanopyrrole were ground in glass growth, mill together with 10 g. of talcum. 10 g. of corn seeds Example 27 Wi,th relatively low vitality were dressed with 50 In the present test the substances according to Examples thls Preparatlon' l dressed seifds (a hundrajd per 1 and 4 have been tested in the same way as described in merit) were garden naturally Infected Wlth 25 the previous Example and the same concentrations have Soil fungi (Pythium -L and kept at in 6105 also been used. The two substances have been tested on bOXeS for 10 y Then the bOXeS Wfife Opened and kept the following micro-organisms: Micrococcus aureus 4, 3 days at 30 C. Escherichia coli 25, Escherichia coli H, Salmonella typhi, In three e pe i 98 and 100% respectively of Proteus vulgaris, Aerobacter aerogenes, Bacillus subtilis, the seeds were germinated. Candida albicans, Aspergillas niger, Penicillium expan- In the following examples, Examples 24 and 25 it will sum, Trichiphyton mentagrophyres, Trichophyton ruburm. be described how two powdery preparations according to The results obtained have been put together in the followthe present application are prepared. ing table.

Test organisms M. E. coli E. coli Sulm. Prot. Aer. Bac. Cami. Asp. Pen. Tri. Tri. our. 4 25 H typhi vugl. aerog. subt. all). niger exp. rubr. merit.

Every figure value states the lowest concentration g/ml. substratum), that has a growth inhibited Substance x. influence after inoculation for 24 hours N-methyl-a,a-dithioeyanopyrrole 1 40 16 40 16 40 40 4 8 4 1 1 a,a'-dithioeyanopyrr0le 2 16 16 16 16 16 40 16 4 16 16 1 2 1 Test solution 4. 2 Test solution 25. 3 Test solution 11.

Example 24 What is claimed is:

1. A method of combatting plant and seed harmful f N- th I -dth1oc ano rrole $122333 iig nii ii soii o r cliemicz a l, 44 o of fung! Plants and Seeds a kaolin g of a fignine sulfonate (polyfon H) and 10 fungicidally effective amount of a compound of the forg. of oleyl N-methyl sodium taurate. This mixture was 50 mula ground in an air mill until 95% of the particles measured less than 325 mesh.

Example 25 In the present example instead of 500 g. N-methyl-a,ot'- dithiocyanopyrrole 250 g. of a,a'-dithiocyanopyrrole was I used, which was mixed and milled together with 650 g. NCS SCN of kaolin, 70 g. of lignine sulfonate (Polyfon H) and 30 g. of a fatty alcohol sulfate (Nifapon).

In the following two examples, Ex. 26 and 27, it will be accounted for the results obtained from tests concerning the bactericidal and fungicidal elfect of some of the substances according to the present application. 1

Example 26 In the present example the substances according to the Examples 1, 2, 3, 6, 7 and 8 have been tested. Five different test concentrations have been "applied viz. 1, 4, 8, cs 5 ON 40 and 100 ig/ml. In the tests four different micro- \N organisms have been used viz. Micrococcus aureus 4, Es- I cherichia coli 6, Candida albicans and Aspergillus niger.

Solutions of the mentioned micro-organisms have been prepared in known way. The purpose of the tests was to establish the lowest concentration of the mentioned substances that inhibited the growth of the microorganisms. 01

9 2. The method of clami 1 wherein the compound is OTHER REFERENCES lid 0 n I'h e i litfiid of claim 1 wherein the compound is g? pp to seeds- Chemical Abstracts, vol. 32, 2560 1938.

References Cited UNITED STATES PATENTS ALBERT T. MEYERS, Pnmary Exammer 2,220,980 11/1940 Horst. D. J. FUNDERBURK, Assistant Examiner 3,231,596 1/1966 Kniisli et a1 260454 US. Cl. X R

3,285,931 11/1966 Huisgen 260326.3 X 71-95 

